E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028228 |
E.1.2 | Term | Multiple myeloma |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Primary Objective : The primary objective is to compare the efficacy of daratumumab when combined with lenalidomide and dexamethasone (DRd) to that of lenalidomide and dexamethasone (Rd), in terms of progression-free survival (PFS) in subjects with newly diagnosed myeloma who are not candidates for high dose
chemotherapy and autologous stem cell transplant. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
- To evaluate clinical outcomes including:
- Time to disease progression (TTP)
- Stringent CR (sCR) rate
- CR rate
- MRD negativity rate
- PFS2 (defined as time from randomization to progression on the next line of therapy or death,
whichever comes first)
- Time to next treatment
- Overall response rate (CR + partial response [PR] rate)
- Proportion of subjects who achieve very good partial response (VGPR) or bette
-Time to response
- Duration of response
- Overall survival |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Subject must be at least 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place).
-Participant must have documented multiple myeloma satisfying the CRAB (calcium elevation, renal insufficiency, anemia and bone abnormalities) criteria, monoclonal plasma cells in the bone marrow greater than or equal to (>=) 10 percent (%) or presence of a biopsy proven plasmacytoma and measurable disease as
defined by any of the following: (a) immunoglobulin (Ig) G myeloma (serum monoclonal paraprotein [Mprotein] level >=1.0
gram/deciliter [g/dL] or urine Mprotein level >=200 milligram[mg]/24 hours[hrs]; or (b) IgA, IgM, IgD, or IgE multiple myeloma (serum Mprotein level >=0.5 g/dL or urine Mprotein level >=200 mg/24 hrs); or (c) light chain multiple myeloma without measurable disease in serum or urine (serum immunoglobulin free light chain >=10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio)
-Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
-Participants who are newly diagnosed and not considered for highdose chemotherapy with SCT due to: being age >=65 years; or participants less than (<) 65 years with presence of important comorbid condition(s) likely to have a negative impact on
tolerability of high dose chemotherapy with stem cell transplantation. Sponsor review and approval of participants below 65 years of age is required before randomization
-Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device [IUD], hormonal [progesterone-only birth control pills or injections or partner’s vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing and must continue for 3 months after the last dose of daratumumab.
Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy
-Man, who is sexually active with a woman of childbearing potential potential must agree to use a latex or synthetic condom, even if he had a successful vasectomy, must agree to use an adequate contraception method as deemed appropriate by the Investigator, and must also agree to not donate sperm during the study, for 4 weeks after the last dose of lenalidomide, and for 3 months after the last dose of daratumumab.
- A woman of childbearing potential must have 2 negative serum or urine pregnancy tests at Screening, first within 10 to 14 days prior to dosing and the second within 24 hours prior to dosing. |
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E.4 | Principal exclusion criteria |
- Participant has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance (presence of serum M-protein <3 g/dL; absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to the M-protein), or smoldering multiple myeloma (asymptomatic multiple myeloma with absence of related organ or tissue impairment end organ damage)
- Participant has a diagnosis of Waldenström’s disease, or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions
- Participant has prior or current systemic therapy or SCT for multiple myeloma, with the exception of an emergency use of a short course (equivalent of dexamethasone 40 mg/day for 4 days) of corticosteroids before treatment.
- Participant has a history of malignancy (other than multiple myeloma) within 5 years before the date of randomization
(exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the Investigator, with concurrence with the Sponsor's medical monitor, is considered cured with minimal risk of recurrence within 5 years)
-Participant has had radiation therapy within 14 days of randomization
- Participant has had plasmapheresis within 28 days of randomization.
-Participant is exhibiting clinical signs of meningeal involvement of multiple myeloma
- Participant has known chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for subjects suspected of having COPD and subjects must be
excluded if FEV1 <50% of predicted normal.
- Participant has had known moderate or severe persistent asthma within the last 2 years or currently has uncontrolled asthma of any classification (controlled intermittent asthma or controlled mild persistent asthma are allowed in the study )
- Participants with known or suspected COPD or asthma must have a FEV1 test during Screening
-Participant is known to be seropositive for history of human immunodeficiency virus (HIV) or known to have active hepatitis B or hepatitis C
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free Survival (PFS) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline for the duration
of disease follow-up, with an
expected average of 40
months |
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E.5.2 | Secondary end point(s) |
1-Time to Disease Progression (TTP)
2-Percentage of Participants With Stringent Complete Response (sCR)
3-Percentage of Participants With Complete response (CR)
4-Progression-Free Survival on Next Line of Therapy (PFS2)
5-Percentage of Participants With Negative Minimal Residual Disease (MRD)
6-Time To Next Treatment
7-Percentage of Participants With Overall Response (OR)
8-Percentage of Participants With Very Good Partial Response (VGPR) or Better Response
9-Duration of Response (DR)
10-Overall Survival (OS)Time
11-European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Score
12-Euro Quality of Life (EQ-5D-5L) Health State Profile Utility Score
13-Time to response |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1,2,3,4,6,7, 8 ,9 , 13- From baseline for the duration of disease follow-up, with an expected average of 40 months
5- From baseline up to 18 months after confirmed CR, with an expected average of 24 months
10- Baseline up to 5 years after last participant is randomized
11 and 12- From baseline up to 16 weeks after disease progression, with an expected average of 44 months |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
daratumumab plus or minus lenalidomide/dexamethasone |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 84 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
Israel |
New Zealand |
United States |
Austria |
Belgium |
Denmark |
France |
Germany |
Ireland |
Italy |
Netherlands |
Sweden |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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LSLV considered as end of study following below:
1. After last patient has access to other course of dara, LSLV will occur and the study can be ended
2. After last subject has discontinued treatment, LSLV will occur and the study can be ended
3. If there are still patients in the long-term phase shortly before 31 Jan 2026, these will need to be transferred to another source of dara. After the last patient is transferred, a LSLV will occur and only then the study can be ended on 31 Jan 2026. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 10 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 10 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 25 |